Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract

Ortiz Bezara, Miguel E.; Thurman, Andrew; Pezzulo, Alejandro A.; Leidinger, Mariah R.; Klesney-Tait, Julia A.; Karp, Philip H.; Tan, Ping; Wohlford-Lenane, Christine; McCray, Paul B.; Meyerholz, David K.

Zoonotically transmitted coronaviruses are responsible for three disease outbreaks since 2002, including the current COVID-19 pandemic, caused by SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding the contributions of virus-receptor interactions. ACE2 is a host ectopeptidase and the receptor for SARS-CoV-2. Despite numerous reports describing ACE2 mRNA abundance and tissue distribution, there remains a paucity of data evaluating ACE2 protein and its correlation with other SARS-CoV-2 susceptibility factors. Here, we systematically examined the human upper and lower respiratory tract using single-cell RNA sequencing and immunohistochemistry to determine receptor expression and evaluated its association with risk factors for severe COVID-19. Our results reveal that ACE2 protein is highest within the sinonasal cavity and pulmonary alveoli, sites of presumptive viral transmission and severe disease development, respectively. In the lung parenchyma, ACE2 protein was found on the apical surface of a small subset of alveolar type II cells and colocalized with TMPRSS2, a cofactor for SARS-CoV2 entry. ACE2 protein was not increased by pulmonary risk factors for severe COVID-19. However, ACE2 protein was increased in children, a demographic with a reduced incidence of severe COVID-19. These results offer new insights into ACE2 localization and function in susceptibility to COVID-19.